Genomic DNA in human cells is hierarchically packaged by histones to form a highly repressive structure of chromatin. The basic unit of chromatin is the nucleosome, which consists of 147-bp of negatively supercoiled DNA wrapped a core histone octamer containing pairs of each of the four core histones, H2A, H2B, H3 and H4. The dynamic posttranslational modifications of histone N-terminal and C-terminal domains (called histone “tails”), which extend away from the nucleosome, govern the structural diversity of chromatin and the accessibility of DNA, thus representing an important molecular mechanism underlying regulation of gene expression. VprBP is a nuclear protein that can interact with HIV viral protein R and the Cullin 4-DDB1 ubiquitin ligase complex. Its cellular function has been studied mainly with respect to its role in regulating Cullin 4 E3 ubiquitin ligase activity and cell cycle progression. However, subsequent studies, predominantly from Inventor's laboratory, have revealed that VprBP stably binds to promoter nucleosomes and that this association represses p53-mediated chromatin transcription (Mol Cell Biol 32, 783-796). The C-terminal region of VprBP has an ability to interact with H3 N-terminal tails protruding from nucleosomes and is critical for the observed functions of VprBP. Overexpression and mutations of VprBP have been detected in bladder/breast/prostate cancer cells supporting the idea that it possesses oncogenic properties.